1. Field of the Invention
Movement disorders affect a significant portion of the population, causing disability as well as distress. This invention concerns the treatment of several movement disorders: 1) tics, including multiple tics and Gilles de la Tourette syndrome (TS); 2) tardive dyskinesia (TD) and related movement disorders induced by exposure to neuroleptic (antipsychotic) drugs; and 3) focal dystonias, including blepharospasm Meige syndrome, torticollis, spasmodic dysphonia, and writer's cramp.
2. Description of the Related Art
Tics are estimated to affect 1% to 13% of boys and 1% to 11% of girls, the male-female ratio being less than 2 to 1. Approximately 5% of children between the ages of 7 and 11 years are affected with tic behavior (Leckman et al., Neuropsychiatry of the Bas. Gang, December, 20(4): 839-861, 1997). The estimated prevalence of multiple tics with vocalization, i.e. Tourette's syndrome, varies among different reports, ranging from 5 per 10,000 to 5 per 1,000. Tourette's syndrome is 3-4 times more common in boys than girls and 10 times more common in children and adolescents than in adults (Leckman et al., supra; Esper et al, Tenn. Med., January, 90:18-20, 1997).
Tardive dyskinesia (TD) affects approximately 15-20% of patients treated with neuroleptic drugs (Khot et al., Neuroleptics and Classic Tardive Dyskinesia, in Lang A E, Weiner W J (eds.): Drug Induced Movement Disorders, Futura Publishing Co., 1992, pp 121-166). Therefore, the condition affects hundreds of thousands of people in the United States alone. The cumulative incidence of TD is substantially higher in women, in older people, and in those being treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (manic-depressive illness) (see, e.g., Hayashi et al., Clin. Neuropharmacol, 19:390, 1996; Jeste et al., Arch. Gen. Psychiatry, 52:756, 1995). Unlike the of the acute motor side effects of neuroleptic drugs, TD does not respond in general to antiparkinson drugs (Decker et al., New Eng. J. Med., October 7, p. 861, 1971).
Focal dystonias are a class of related movement disorders involving the intermittent sustained contraction of a group of muscles. The most common is spasmodic torticollis, which involves twisting of the neck. Other examples are blepharospasm, which involves involuntary eye closure, and writer's cramp, which involves contraction of the muscles of the hand. The prevalence of focal dystonias in one US county was estimated as 287 per million (Monroe County Study); this suggests that at least 70,000 people are affected in the US alone.
Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by involuntary, irregular rhythmic movements of the mouth, tongue, and facial muscles. The upper extremities also may be involved. These movements may be accompanied, to a variable extent, by other involuntary movements and movement disorders. These include rocking, writhing, or twisting movements of the trunk (tardive dystonia), forcible eye closure (tardive blepharospasm), an irresistible impulse to move continually (tardive akathisia), jerking movements of the neck (tardive spasmodic torticollis), and disrupted respiratory movements (respiratory dyskinesia). The vast majority of TD cases are caused by the prolonged use of antipsychotic drugs (neuroleptics). A relatively small number are caused by the use of other medications, such as metoclopramide, that, like neuroleptics, block dopamine receptors. TD often manifests or worsens in severity after neuroleptic drug therapy is discontinued. Resumption of neuroleptic therapy will temporarily suppress the involuntary movements, but may aggravate them in the long run.
TD is also associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning. (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol. Med. 26:681, 1996; Swartz, Neuropsychobiology 32:115, 1995). The cognitive impairment associated with TD usually is seen as a marker of underlying differences in brain function that predispose the patient to TD. However, it may also be due to the TD itself, and may be either irreversible, or partially reversible if the TD is successfully treated.
The pathophysiology of TD has not been established definitively. It is well known that blockade of dopamine receptors will lead to an increased number of dopamine receptors, and therefore to an increased sensitivity to dopamine of striatal neurons. (see, e.g. Andrews, Can J Psych 39:576, 1994; Casey, in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). The first major hypothesis about the pathophysiology of TD was that TD was the result of this hypersensitivity of striatal neurons to dopamine. In support of the “dopamine supersensitivity” hypothesis, it is noted that dopamine agonists can aggravate the disorder (Bezchibnyk-Butler & Remington, Can J. Psych., 39:74, 1994). However, the dopamine supersensitivity hypothesis is not compatible with the observation that TD and Parkinsonism (a dopamine deficiency state) infrequently exist together in the same patient.
Other studies have suggested that irreversible cases of TD may be related to excitotoxic damage to the basal ganglia (Andreassen & Jorgensen, Pharmacol. Biochem. Behav., 49(2):309-312, 1994; Tsai et al.,: Am J Psych, September 155:9, 1207-13, 1998). An acquired deficiency of the inhibitory neurotransmitter GABA has also been implicated in the development of TD (Delfs et al. Experimental Neurol., 133:175-188, 1995).
A widely-studied animal mode of TD, that of vacuous chewing movements (VCM) in rats, has also yielded evidence for a glutamate-based excitotoxic mechanism in the development of the disorder (Meshul et al; Psychopharmacology (Berl), 125:238-47, 1996 June; Andreassen et al; Br J Pharmacol, 199:751-7, 1996 October) When administered to rats with VCM, ethanol acutely decreases the animals' orofacial movements. This effect is prevented if the rats are pre-treated with a benzodiazepine inverse agonist, suggesting that it is mediated by stimulation of GABA-A receptors by ethanol (Stoessl, Pharmacol. Biochem. Behav. July, 54:541-6, 1996 July) Stoessl suggests that “GABAergic stimulation” deserves further investigation in the treatment of TD. He does not, however, advance the idea of treating TD with combined GABA agonism and NMDA antagonism, nor suggest using acamprosate as a treatment for TD.
The physical manifestations of TD can resemble movement disorders associated with degenerative diseases such as Huntington's disease and Parkinson's disease. Patients with TD can show chorea (quick, irregular movements of the extremities) indistinguishable from that seen in cases of Huntington's disease. Neck, trunk and limb movements of TD can be indistinguishable from those of the “peak-dose dyskinesia” associated with prolonged treatment of Parkinson's disease with levodopa.
Recent research suggests that Vitamin E can reduce symptoms of TD modestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri et al. Am. J. Psychiatry, June, 151(6):925-926, 1994). GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD, probably because their low toxicity justifies their use despite their limited efficacy. (Gardos & Cole, Psychopharmacology: The Fourth Generation of Progress, eds. Bloom and Kupfer, pp. 1503-1510, 1995). This review only cited reports of variable benefits associated with other agents including propranolol, clonidine, cholinergic agonists, buspirone and calcium-channel antagonists. However, none of these has become a generally accepted treatment for either the movement or cognitive disorders associated with TD.
In U.S. Pat. No. 5,602,150, by Lidsky et al., it was proposed that co-administration of taurine or taurine derivatives together with neuroleptics, might prevent the emergence of tardive movement disorders, on the theory that the latter are due to excitotoxic damage against which taurine would protect. The recommendation of taurine is based on studies in a single animal model. The experiments reported do not deal with any therapeutic effects of taurine on established movements, either in the presence of continued neuroleptic therapy or otherwise. Neither the patent nor the experiments cited in it predict or imply that taurine or derivatives will be beneficial for established movement disorders. Moreover, the mechanism proposed by Lidsky et al., (supra) is based on long-term neuroprotection. He neither asserts, infers, or suggests that taurine or derivatives might have any immediate, short term effect on movement disorders.
In co-pending, commonly-owned applications Ser. Nos. 08/861,801 and 09/006,641, incorporated herein by reference, treatments with memantine (a congener of amantadine and a N-methyl-D-aspartate type (NMDA) receptor blocker as well as a dopamine agonist), and acamprosate (a calcium salt of a derivative of the amino acid taurine and a NMDA-type receptor blocker as well as a agonist), were advanced as effective treatments for both the movement and cognitive disorders associated with TD, and were reported to be dramatically effective in several severely affected individuals.
A tic is an abrupt repetitive movement, gesture, or utterance that often mimics a normal type of behavior. Motor tics include movements such as eye blinking, head jerks or shoulder shrugs, but can vary to more complex purposive appearing behaviors such as facial expressions of emotion or meaningful gestures of the arms and head. In extreme cases, the movement can be obscene (copropraxia) or self injurious. Phonic or vocal tics range from throat clearing sounds to complex vocalizations and speech, sometimes with coprolalia (obscene speech) (Leckman et al., supra). Tics are irregular in time, though consistent regarding the muscle groups involved. Characteristically, they can be suppressed for a short time by voluntary effort.
Gilles de la Tourette syndrome (TS) is the most severe tic disorder. Patients with TS have multiple tics, including at least one vocal (phonic) tic. TS becomes apparent in early childhood with the presentation of simple motor tics, for example, eye blinking or head jerks. Initially, tics may come and go, but in time tics become persistent and severe and begin to have adverse effects on the child and the child's family. Phonic tics present, on average, 1 to 2 years after the onset of motor tics. By the age of 10, most children have developed an awareness of the premonitory urges that frequently precede a tic. Such premonitions may enable the individual to voluntary suppress the tic, yet premonition unfortunately adds to the discomfort associated with having the disorder. By late adolescence/early adulthood tic disorders can improve significantly in certain individuals. However, adults who continue to suffer from tics often have particularly severe and debilitating symptoms. (Leckman et al., supra).
The pathophysiology of tic disorders like, that of TD, has not yet been established, although several plausible hypotheses have been set forth. Excessive activity of a cortical-striatal-pallidal-thalamic-cortical sensorimotor loop has been implicated in the lack of motor impulse control associated with tic disorders (Ziemann et al., Am. J. Psychiatry, Vol 154, September, 1997; Leckman et al., supra). This hyperactivity may reflect excessive dopaminergic activity in the striatum, or a relative deficiency of inhibitory transmission. While dysfunction of the basal ganglia or their connections is likely to be present, the basal ganglia, thalamus, and motor cortex are anatomically normal in most cases.
Patients with moderate to severe motor and vocal tics are likely to require drug therapy. Many classes of neurological and psychiatric medications have been tried, but only neuroleptics, alpha-2 adrenergic agonists, and clonazepam have attained the status of standard treatments. (For recent reviews see Chappell et al., Neur. Clin. of North Am., 15(2), May 1997; Kurlan, Neurol. Clin., May, 15:403-409, 1997; Lichter et al., J. Child Neur., 11(2), March, 1996; Leckman et al., supra; Esper et al, Tenn. Med., January, 90:18-20, 1997; Scahill et al., J. Child Adolesc Phychopharcmacol, 7(2), 1997; incorporated herein by reference). Unfortunately, all three of the commonly-used treatment for TS have significant drawbacks.
The most common therapies used for the treatment of tic disorders are the neuroleptics (i.e. dopamine antagonist antipsychotic drugs). Within this category, haloperidol and pimozide are most often used in the United States. Neuroleptic treatment usually will suppress the involuntary movements of tic disorders, with up to 85% of patients experiencing relief—(Esper et al., supra). The side effects of neuroleptic drugs include sedation, depression, parkinsonism, cognitive impairment, and tardive dyskinesia. Other tardive movement disorders can develop with prolonged use. The intolerability of side effects often leads patients to discontinue neuroleptic therapy for TS, while the risk of TD makes most physicians unwilling to use them in milder cases. Those with more severe TS must often make an unpleasant choice between distressing symptoms and distressing side effects. People with simple tics may experience emotional distress, embarrassment, impaired self-esteem, or physical injury if their tics are sufficiently violent. Yet, they usually will not be treated with neuroleptics because their side effects and long-term toxicity that are not acceptable in the treatment of relatively mild cases.
Other drug treatments for TS do not carry the risk of TD. But they are less efficacious than neuroleptics. The most common non-neuroleptic alternatives are alpha-2 adrenergic agonists such as clonidine. Unfortunately, fewer than 50% (perhaps as few as 25%) of patients treated with clonidine show clinically significant improvement of tic-related symptoms (Esper et al., supra; Chappell et al., supra). Further, many patients whose tics do respond to clonidine will have side effects that limit its use, most often hypotension or sedation.
Another non-neuroleptic treatment, clonazepam, a benzodiazepine with GABA-A and serotonergic actions, has some efficacy in the treatment of Tourette's syndrome (Steingard et al., J. Am Acad Child Adolesc Psychiatry, March-April, 33:394-9, 1994). Sedation and ataxia limit the dosage of clonazepam; the tolerable dose often is below that needed to suppress the patient's tics.
A new class of compounds that act as antagonists of brain serotonergic 5-HT2 receptors initially showed promising results, although children and adolescents experience increase in sensitivity to side effects. (Chappell et al., supra). Additional alternatives that have received recent attention include antioxidant treatment (Rotrosen et al., Prost. Leuk. and Ess. Fatty Acids, 55(1 & 2), 1996), transcranial magnetic stimulation (Ziemann et al., supra), nicotine treatment (Sanberg et al., Pharmacol. Ther., 74(1)., 1997; Silver et al., J. Am. Acad. Adolesc. Psychiatry, Vol 35, December, 1996) and botulinum toxin treatment (Esper et al., supra). While each of these treatments has offered clinically significant relief to individual patients, none has replaced neuroleptics as the treatment of choice. Clearly, there is a need for additional treatments for tics and TS that do not carry the side effects and long term risks of neuroleptics.
It has been suggested, on theoretical grounds, that future therapies for Tourette's syndrome might include glutamate antagonists, although a recent article proposing their use makes no mention of any specific drugs that might fulfill this role (Chappell et al., Neurol. Clin. May, 15(2):429-450, 1997). 4).
A focal dystonia is a recurrent abnormal posturing of some part of the body. The spasms of focaldystonia can last many seconds at a time, causing major disruption of the function of the affected area. Some of the focal dystonias are precipitated by repetitive movements; writer's cramp is the best known example. Focal dystonia can involve the face (e.g., blepharospasm, mandibular dystonia), the neck (torticollis), the limbs (e.g., writer's cramp), or the trunk. Dystonia can occur spontaneously or can be precipitated by exposure to neuroleptic drugs and other dopamine receptor blockers (tardive dystonia). No systemic drug therapy is generally effective, but some drugs give partial relief to some patients. Those most often prescribed are anticholinergics, baclofen, benzodiazepines, and dopamine agonists and antagonists. The most consistently effective treatment is the injection of botulinum toxin into affected muscles.
Positron emission tomography has shown that one specific dystonia, torticollis, is associated with neuronal hypermetabolism in the basal ganglia. It has been hypothesized that hyperactivity of a motor control loop involving the cerebral cortex, basal ganglia, and thalamus is responsible for the abnormal postures and movements (i.e. movements into and out of abnormal postures) characteristic of dystonia (Galardi et al., Acta. Neurol Scand, September, 94:172-6, 1996). Other studies have shown abnormal dopaminergic transmission or receptor function in patients with dystonia (see, e.g. Perlmutter et al., J Neurosci, January 15, 17:843-50, 1997). Of note, both too much or too little dopamine may be associated with dystonia, since patients with Parkinson's disease and dystonia can have the problem both at peak and trough levels of levodopa (Hallett, Arch. Neurol. May, 55:601-3, 1998). It is evident that similar mechanisms may be involved in the pathophysiology of tic disorders and focal dystonias.
The various focal dystonias tend to respond to the same drugs (Chen, Clin. Orthop, June, 102-6, 1998; Esper et al; Tenn. Med, January, 90:18-20, 1997; De Mattos et al., Arq. Neuropsychiatry, March 54:30-6, 1996) This suggests that a new treatment helpful for one focal dystonia would be likely to be helpful for another. Furthermore, the common symptoms, signs, and responses to medication of spontaneous (idiopathic) dystonia and neuroleptic-induced dystonia suggest that an effective treatment for a drug-induced focal dystonia will be effective for the same dystonia occurring spontaneously.
Blepharospasm, one of the focal dystonias, is a condition that involves continually recurring involuntary eye closure or excessive forceful blinking. Blepharospasm is one of the most common disorders of oculomotor function. It is variably regarded as a facial dyskinesia or a facial dystonia. When it occurs together with dystonia of the oral and mandibular regions, with or without involvement of the neck, it is referred to as Meige syndrome. Blepharospasm can significantly impair visual function. Patients can become unable to read, to drive an automobile, or to do any skilled work requiring visual control. Blepharospasm can occur spontaneously (idiopathic blepharospasm) and with a prevalence that increases with increasing age; most cases arise in the fifth and sixth decades of life (Holds et al., Am. Fam. Physician, June, 43:2113-20, 1991). It also can occur as a sequel to neuroleptic drug treatment (Ananth et al., Am. J. Psychiatry, April, 145:513-5, 1988; Kurata et al., Jpn. J. Psychiatry. Neurol., December, 43:627-31, 1989; Sachdev et al., Med. J. Aust., March 20, 150:341-3, 1989) and perhaps treatment with other classes of psychotropic drugs (Mauriello et al., J Neuropathol, June, 18:153-7, 1998), either alone or in conjunction with tardive dyskinesia or tardive dystonia. Another report of 19 patients with severe tardive dyskinesia, stated that frequent eye blinking was the most frequent prodromal sign of the disorder (Gardos et al., supra, 1988). The oculomotor phenomena of idiopathic blepharospasm and Meige syndrome are identical with those seen in cases induced by neuroleptic treatment. Differences between idiopathic blepharospasm and tardive blepharospasm do not involve the ocular movements themselves. Patients with idiopathic blepharospasm are more likely to have a family history of movement disorders, and those with tardive blepharospasm are more likely to have movements of other parts of the body.
Though many substances have been tested for their ability to relieve blepharospasm, injection of botulinum toxin into orbicularis oculi muscles is the mainstay of treatment—(Mauriello et al., Br. J. Ophthalmol, December, 80:1073-6, 1996). These injections weaken the muscles responsible for eye closure, thereby mitigating the involuntary movements of those muscles. They may also indirectly influence oculomotor control by the central nervous system, by altering the input from motor nerve afferents. Botulinum toxin injections have become treatment of choice because of the limited efficacy of the numerous systemic drug treatments tried to date.
Movements associated with blepharospasm “do not respond to systemic drug treatment”. In one large case series, only 22% of blepharospasm patients treated with systemic medications got “marked and persistent relief” (Jankovic et al., Mov. Disord., May, 9:347-349, 1983). In another report, of the 13 patients with blepharospasm who did not do well with botulinum toxin injections, only 2 showed any improvement when given systemic drug therapy (Mauriello et al., Clin. Neurol. Neurosurg., August, 98:213-6, 1996)). Even botulinum toxin injections are not always efficacious. Surgery is sometimes recommended for patients who do not get relief from botulinum toxin injections (Elston et al., J. Neurol, January, 239:5-8, 1992).
Of the systemic treatments, (see, for example, Arthurs et al., Can. J. Ophthalmol: February, 22:24-8, 1987; Casey et al., Neurology, July, 30:690-5, 1980; Jacoby et al., Invest. Ophthalmol. Vis. Sci., March, 31:569-76, 1990; Michaeli et al., Clin. Neuropharmacol., June, 11:241-9, 1988; Ransmayr et al., Clin. Neuropharmacol., February, 11:68-76, 1988; clonazepam, a GABA agonist, was the only drug consistently found useful (Jankovic et al., Ann. Neurol., April, 13:402-11, 1983). A combination of two GABA agonist agents, valproate and baclofen, was efficacious in a single case (Sandyk, et al., S Afr Med J, December, 64:955-6, 1983). Tetrabenazine, a dopamine depleting agent, alleviated involuntary movements in 4 of 6 patients with Meige syndrome, but the patients had many undesirable side effects including drowsiness, drooling and Parkinsonism (Jankovic, et al., Ann Neurol, January, 11:41-7, 1982). Because of such unpleasant side effects, tetrabenazine has not become a widely-used treatment for blepharospasm, tics or even tardive dyskinesia, despite the absence of other generally effective treatments for these conditions. In sum, though GABA agonists and dopamine receptor blockers have been employed with some benefit in the treatment of idiopathic blepharospasm, neither type of medication has proved to be a generally satisfactory treatment.
Because magnesium deficiency can cause neuromuscular excitability (Durlach et al, Magnes Res, June, 10:169-95, 1997), it could potentially cause or aggravate movement disorders. Ploceniak, (Communications Libres, 91, suppII, 1990) reported, without details, that he had found magnesium supplementation useful in patients with bruxism (teeth grinding) and facial tics associated with tetany (susceptibility to muscle cramps typical of hypocalcemia). He did not, however, suggest that magnesium supplementation would help patients with Tourette's syndrome, or those with tics not due to magnesium deficiency.
There is considerable evidence for abnormalities of magnesium status in patients with severe mental illness (see for example, Athanassenas et al., J. Clin. Psychopharmacol. August, 3:212-6, 1983; Alexander et al., Br. J. Psychiatry, August, 133:143-9, 1978; Kirov et al., Neuropsychobiology, 30(2-3):73-78, 1994; Wang et al, 1997; Yassa et al., Int Pharmacopsychiatry, 14(1):57-64, 1979). Alexander et al. (supra, 1978) found that those schizophrenic patients developing extrapyramidal side effects from neuroleptics had, on average, lower magnesium levels than those not having such side effects. Neuromuscular excitability and anxiety are common acute manifestations of magnesium depletion. And, there are theoretical reasons to speculate that magnesium deficiency may contribute to a wide range of neurodegenerative disorders (Durlach et al. 1997, supra). However there has been no suggestion that magnesium deficiency is a cause of tardive dyskinesia, tics, Tourette's syndrome or blepharospasm or that magnesium supplementation can be used to successfully treat or prevent movement disorders.
Although the present day pharmacopeia offers a variety of agents to treat movement disorders, none of these agents can prevent or cure these conditions. Furthermore, the most effective treatments are often associated with intolerable side effects. There remains a clear-cut need for new treatments for TD, other tardive movement disorders, tics, Tourette's syndrome, blepharospasm, and other focal dystonias that have greater efficacy and fewer side effects than those currently available.